MOLECULAR ENGINEERING OF MONOCLONAL ANTIBODIES FOR THE MANAGEMENT OF CANCER

用于癌症治疗的单克隆抗体分子工程

• 批准号: 5209123
• 负责人: SHUI-ON LEUNG
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5209123
• 关键词: antitumor antibody; chimeric proteins; colorectal neoplasms; human genetic material tag; immunoconjugates; immunoglobulin G; molecular cloning; monoclonal antibody; nucleic acid sequence; pancreas neoplasms; pharmacokinetics; protein engineering; radiotracer; transfection

Several problems limiting the use of monoclonal antibodies (MAbs) for the diagnosis and therapy of diseases are addressed using the techniques of molecular biology. The approaches of humanization will be undertaken in an attempt to reduce the immunogenicities elicited by multiple injections of rodent antibodies. The MAbs used for this research include PAM4 (anti-pancreatic cancer), MN-14 (anti-colorectal cancer) and Mu-9 (anti-colorectal cancer), which have been demonstrated to have significant clinical utilities. Favorable pharmacokinetic and biodistribution characteristics, such as faster blood clearance, lower liver and kidney uptake, etc., will be engineered in MAbs. This can be achieved by the deletion of the CH2 domain from the whole IgG molecule. Humanized MN-14 antibody will be used as the prototype for the initial construction and evaluation of this new form of MAb. Moreover, to facilitate and increase the loading capacity for radiolabeling, whole IgG or F(ab')2 fragments containing an IgG3 hinge region, instead of that of IgG1, will be constructed. The improvement in the ease of labeling and radioisotope loading capacity of the IgG3 hinge-containing molecules will be compared to those carrying the IgG1 hinge regions. Hopefully, a humanized, CH2-deleted antibody with a long IgG3 hinge region will serve as a non-immunogenic, highly radioactive biopharmaceutical that can be used repeatedly for the treatment for diseases, without undesirable accumulations in normal tissues and organs. Large quantities of these recombinant MAbs are required for their clinical efficacy assessment; however, the current system for production of MAbs is inadequate. New DNA vectors and transfection protocols will be developed to allow for high level of expression of the recombinant MAbs in a bioreactor.

限制单克隆抗体（MAbs）用于 疾病的诊断和治疗是使用这些技术来解决的， 分子生物学。 将采取人性化的方法 为了减少由多种免疫原性引起的免疫原性， 注射啮齿动物抗体 用于本研究的MAb 包括PAM 4（抗胰腺癌）、MN-14（抗结肠直肠癌） 和Mu-9（抗结肠直肠癌），已被证明具有 显着的临床效用。 良好的药代动力学和 生物分布特性，如更快的血液清除，更低的 肝脏和肾脏摄取等，将在MAb中进行工程化。 这可以 通过从整个IgG分子中缺失CH 2结构域来实现。 人源化MN-14抗体将被用作用于初始免疫的原型。 构建和评价这种新形式的MAb。 此外，为了 促进和增加放射性标记的装载能力， 含有IgG 3铰链区的IgG或F（ab '）2片段，而不是 IgG 1，将被构建。 在方便性方面的改进 含IgG 3铰链的标记和放射性同位素负载能力 分子将与携带IgG 1铰链区的那些进行比较。 有希望的是，具有长IgG 3铰链的人源化CH 2缺失抗体 该区域将作为一个非免疫原性，高放射性 可重复用于治疗的生物药物， 疾病，在正常组织中没有不期望的积累， 机关 需要大量的这些重组单克隆抗体， 他们的临床疗效评估;然而，目前的系统 单克隆抗体的产量不足。 新的DNA载体和转染 将开发方案以允许高水平表达 在生物反应器中的重组MAb。